A CRISPR-Cas9 repressor for epigenetic silencing of KRAS.

Pharmacological Research : the Official Journal of the Italian Pharmacological Society
Jingwen LiuBin Guo

Abstract

KRAS is one of the most frequently mutated oncogenes in cancers. Currently no direct and effective anti-KRAS therapies are available. Using the powerful CRISPR-Cas9 technology to target the mutant KRAS promoter, we designed an epigenetic repressor to silence KRAS through epigenome editing. Catalytically dead Cas9 (dCas9) functioned as a DNA binding device, which was fused with a transcriptional repressor histone deacetylase 1 (HDAC1). We designed a panel of three CRISPR RNAs (crRNAs) covering 1500-bp range of the KRAS promoter and identified that crRNA1 and crRNA2 efficiently silenced KRAS. The suppression of K-Ras resulted in a significant inhibition of cell growth, suppression of colony formation in soft agar and induction of cell death in cancer cells with KRAS mutations. In addition, the chromatin immunoprecipitation (ChIP) assay demonstrated dCas9-HDAC1 modified histone acetylation on the KRAS promoter. Furthermore, transfection of dCas9-HDAC1 protein and gRNA ribonucleoprotein complex also inhibited K-Ras and suppressed cell proliferation. In summary, we have developed a new strategy that combines CRISPR-Cas9 technology with HDAC1 epigenetic silencing to target cancers driven by KRAS mutations.

References

Jun 1, 1991·Proceedings of the National Academy of Sciences of the United States of America·S KajigayaN S Young
May 9, 1998·Proceedings of the National Academy of Sciences of the United States of America·C A HassigS L Schreiber
Feb 28, 2007·Cell Research·Paola GallinariChristian Steinkühler
Feb 28, 2008·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Jenifer L MarksWilliam Pao
Jun 24, 2008·Nature Reviews. Molecular Cell Biology·Antoine E Karnoub, Robert A Weinberg
Feb 13, 2010·The EMBO Journal·Matthias DrostenMariano Barbacid
Nov 26, 2010·Nature Reviews. Cancer·Dominico VigilChanning J Der
Jul 23, 2011·Genes & Cancer·Esther Castellano, Eugenio Santos
Oct 14, 2011·Nature Reviews. Cancer·Yuliya Pylayeva-GuptaDafna Bar-Sagi
Oct 25, 2011·Nature Reviews. Cancer·Norbert BerndtSaïd M Sebti
Mar 21, 2012·Proceedings of the National Academy of Sciences of the United States of America·Till MaurerGuowei Fang
May 29, 2012·Cell·Scott J DixonBrent R Stockwell
Jun 27, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Sabine TejparEric Van Cutsem
Oct 30, 2012·Nature·Andrew V BiankinSean M Grimmond
Jul 31, 2013·Nature Methods·Pablo Perez-PineraCharles A Gersbach
Jun 25, 2014·Nature Reviews. Cancer·Matthew HolderfieldMartin McMahon
Oct 18, 2014·Nature Reviews. Drug Discovery·Adrienne D CoxChanning J Der
Apr 10, 2015·Nature Reviews. Genetics·Ophir ShalemFeng Zhang
Jul 21, 2015·Journal of Biotechnology·Emily M AndersonAnja van Brabant Smith
Oct 6, 2015·Nature Biotechnology·James E DahlmanSilvana Konermann
Feb 4, 2016·Science·Fuguo JiangJennifer A Doudna
Feb 6, 2017·Molecular Cancer·Tan Boon TohEdward Kai-Hua Chow
Mar 7, 2017·Bioconjugate Chemistry·Rubul MoutVincent M Rotello
May 6, 2017·Nature Communications·David W MorgensMichael C Bassik
Jul 18, 2018·Nature Methods·Nan Cher YeoGeorge M Church
Oct 26, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ken SuzawaRomel Somwar
Sep 8, 2019·Nature Communications·Josh TyckoMichael C Bassik

❮ Previous
Next ❯

Citations

Apr 10, 2021·Journal of Zhejiang University. Science. B·Chao LiBaohong Zhang

❮ Previous
Next ❯

Related Concepts

Related Feeds

CRISPR (general)

Clustered regularly interspaced short palindromic repeats (CRISPR) are DNA sequences in the genome that are recognized and cleaved by CRISPR-associated proteins (Cas). CRISPR-Cas system enables the editing of genes to create or correct mutations. Discover the latest research on CRISPR here.

CRISPR Ribonucleases Deactivation

CRISPR-Cas system enables the editing of genes to create or correct mutations. This feed focuses on mechanisms that underlie deactivation of CRISPR ribonucleases. Here is the latest research.

CRISPR in Cancer

CRISPR-Cas system enables the editing of genes to create or correct mutations. Given that genome instability and mutation is one of the hallmarks of cancer, the CRISPR-Cas system is being explored to genetically alter and eliminate cancer cells. Here is the latest research.

Related Papers

Current Topics in Medicinal Chemistry
Hai-Zhou WuYan Cheng
Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer
Alex A Adjei
© 2021 Meta ULC. All rights reserved